J. Pediatr. (Rio J.) vol.83 no.1 Porto Alegre Jan./Feb. 2007

http://dx.doi.org/10.2223/JPED.1585

There has been
a remarkable increase in interest during the past two decades in the relation
between cardiovascular risk factors in children and the development of arteriosclerotic
cardiovascular disease (ASCVD) and type 2 diabetes in adulthood. Initial studies
concentrated on individual factors such as lipids and blood pressure. However,
as research in this area has evolved and pediatricians have followed the lead
of their colleagues in internal medicine, attention has turned to broader considerations
of risk and, in particular, to obesity, insulin resistance and the metabolic
syndrome. It is not surprising that these studies are affirming the concept
that the roots of ASCVD and type 2 diabetes extend back into childhood.

The relation of
obesity to ASCVD in adults is well known. Although children and adolescents
do not have overt ASCVD, obese children have a cardiovascular risk profile consistent
with its early development, i.e., significantly higher blood pressure, triglycerides
and fasting insulin and significantly lower HDL-C.1 Moreover, the
degree of risk increases with increasing obesity.2 The result is
early deposition of fatty streaks and plaque in adolescent coronary arteries,3
and the outcome in adulthood is an increased incidence of premature cardiovascular
and all-cause mortality in individuals who were obese adolescents.4
Despite a perception in the general population that overweight children tend
to become thinner as they go through adolescence and maintain the thinness as
they become young adults, longitudinal growth studies have shown a highly significant
(r = 0.61) correlation in body mass index (BMI) between ages 7 and 24, and have
further shown that BMI at age 7 predicts the ASCVD risk factors at age 24.5
The relevance of these findings is of increasing importance to pediatricians,
since the prevalence of obesity in children is steadily increasing in all ethnic
groups.6

The relation of
obesity to insulin resistance is also well known, and while insulin resistance
is related to the development of ASCVD, its role independent from obesity is
not clearly defined. Nevertheless, it has become evident that obesity cannot
completely explain the development of insulin resistance. Insulin resistance
is not present in all obese individuals; nonobese, nondiabetic individuals can
be insulin-resistant; and type 2 diabetes occurs in nonobese individuals. In
an attempt to clarify the independent influence of BMI and insulin resistance
on the development of cardiovascular risk and type 2 diabetes, we have been
conducting a longitudinal study, including euglycemic hyperinsulinemic clamps,
in children who were randomly recruited from a public school population of 11-14
year olds. Results from this study are showing that insulin resistance, of itself,
is associated with increased levels of cardiovascular risk factors.1
When the cohort was divided into two groups according to insulin sensitivity
and resistance, the insulin resistant group was found to have significantly
higher fasting insulin, triglycerides and lower HDL-C, independent of BMI. And,
when the cohort was further divided according to levels of both BMI and insulin
resistance, an interaction was uncovered in the obese, insulin resistance group,
leading to higher levels of risk factors than would be expected by simply adding
together the individual effects of BMI and insulin resistance. This cohort has
now been followed to early young adulthood (age range 18-21). Recent studies7
have shown that insulin resistance measured at age 13 predicts, independent
from BMI, blood pressure and lipids at age 19. Thus, it appears that insulin
resistance, of itself, is etiologically related to the ultimate development
of ASCVD.

As investigation
into the relation between obesity and insulin resistance has intensified, certain
fat compartments, in particular visceral fat, have been shown to be more functionally
active than others.8 Visceral fat cells have higher rates of lipolysis
than subcutaneous fat cells, resulting in a greater production of free fatty
acids, and elevated free fatty acids have been associated with increased insulin
resistance. In addition, visceral fat is a prominent source of the adipocytokines
Il-6, TNF-α and adiponectin, all of which have been related to insulin
resistance. Visceral fat content is highly correlated with waist circumference,
suggesting that waist, rather than BMI, may be a better predictor of insulin
resistance.

In this issue of
Jornal de Pediatria Ferreira et al.,9 report on the prevalence of
the metabolic syndrome in 1,550 Brazil schoolchildren. They found that 8% of
the children were overweight, and 17.3% of the overweight children had the metabolic
syndrome. Although these figures are lower than those reported for Caucasian,
Black and Hispanic children in the United States,6,10 they show that
Brazil is faced with the same high prevalence seen in other countries. The appropriate
application of the metabolic syndrome to patient care is still being debated,11
but most would agree that it is related clinically to future cardiovascular
disease. Although a direct role for insulin resistance in the development and
maintenance of the syndrome has not been established, most clinicians believe
insulin resistance is directly involved. It might be suggested that obese children
without the metabolic syndrome are those without insulin resistance. An issue
for pediatrics is how to define threshold values for the factors comprising
the system. Most studies in children have arbitrarily modified the published
adult standards to select values that are based on pediatric norms. This is
a reasonable approach, but longitudinal studies confirming the appropriateness
of those values have not yet been published.

The euglycemic
hyperinsulinemic clamp is the acknowledged "gold standard" measure
of insulin resistance.12 In the study by Ferreira et al., the authors
use HOMA, a surrogate measure of clamp-derived insulin resistance, to show an
apparent link between the metabolic syndrome and insulin resistance. Because
the clamp is technologically more complicated and places an increased burden
on the patient, including a 2-3 hour stay in a clinical research center, a number
of surrogate measures for insulin resistance have been designed. HOMA is one
of the most widely used and requires only a fasting blood sample for insulin
and glucose. The formula for HOMA is serum glucose x fasting insulin/22.5. However,
HOMA does not define insulin resistance in children with any greater accuracy
than fasting insulin (the correlation between fasting insulin and HOMA is >
0.95), because glucose is so tightly controlled and its range is so narrow in
children that its use in the HOMA formula does not discriminate among individuals.
The correlation between either HOMA or fasting insulin and the insulin clamp
is low (approximately 0.4-0.5 in most studies), and most investigators today
do not believe that HOMA is an accurate measure of insulin resistance in children.

Can fasting insulin
be used as a surrogate measure for insulin resistance? Unfortunately, the range
of fasting insulin in children is relatively narrow, so that it also lacks the
precision required to categorize individuals. However, degree of insulin secretion
is relevant to the study of insulin resistance, and fasting insulin levels may
be used in other ways. For instance, it has been incorporated by the European
Group for the Study of Insulin Resistance into the definition for the metabolic
syndrome.13 In our studies in children we have incorporated it with
triglycerides, HDL-C and blood pressure into an "insulin resistance score"
that has been applied in studies of BMI and insulin resistance.1
We have found that the score may provide a better picture of overall cardiovascular
risk than examination of the individual risk factors.

Physicians caring
for children have historically been entrusted with preventing disease during
childhood and ensuring normal growth and development prior to adulthood. The
soaring prevalence of obesity in childhood coupled with the increase in levels
of cardiovascular risk factors and the metabolic syndrome offers another challenge
to fulfilling those responsibilities. Although it has been obvious for many
years that obesity is associated with cardiovascular risk, the etiologic factors
linking obesity to the factors that define the metabolic syndrome have not been
identified. Recent data suggest that insulin resistance may be one of those
factors. It is hoped that ongoing studies in children will provide the information
required to design strategies that can be applied during childhood in order
to reduce the incidence of premature ASCVD in adults.

11. Kahn R, Buse
J, Ferrannini E, Stern M; American Diabetes Association; European Association
for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal:
joint statement from the American Diabetes Association and the European Association
for the Study of Diabetes. Diabetes Care. 2005;28:2289-304.